1. Field of the Invention
This invention relates to biomedical devices, and more specifically relates to a method for coating a substrate with an antithrombogenic and/or an anti-infective agent.
2. Background of the Invention
Extensive investigations have been undertaken over many years to find materials that will be biologically and chemically stable toward body fluids. This area of research has become increasingly important with the development of various objects and articles which can be in contact with blood, such as artificial organs, vascular grafts, probes, cannulas, catheters and the like.
Synthetic plastics have come to the fore as preferred materials for such articles. However, these materials have the major drawback of being thrombogenic. Thrombogenicity has conventionally been counteracted by the use of anticoagulants such as heparin. Various procedures for attachment of heparin to otherwise thrombogenic polymeric surfaces have been disclosed.
U.S. Pat. No. 4,521,564 to Solomon et al. discloses coating a polymeric article with an amine-rich surface and covalently conjugating aldehyde-actuated heparin to the amino groups thereof. Leininger et al., in U.S. Pat. No. 3,617,344 discloses a method in which a polymeric surface is chemically modified to include a chloromethyl group. Amination of the chloromethyl group provides a quarternary ammonium halide. Reaction of the halide with sodium heparin results in ionic bonding of the heparin to the surface.
A related approach has been described by Eriksson et al. in U.S. Pat. No. 3,634,123. An article having a plastic surface is heated to near or above its softening point in an aqueous solution of a cationic surface active agent, such as a long chain alkylamine or alkylenediamine hydrohalide. The solution is preacidified to a pH of 7.0 or lower. Subsequent digestion of the plastic article with an aqueous solution of heparin results in an article having about 0.1 International Unit of heparin thereon.
A further improvement is described in U.S. Pat. No. 3,810,781 to Eriksson et al., wherein heparinized plastic surfaces are stabilized with glutaraldehyde.
Williams et al., in U.S. Pat. No. 4,349,467 discloses a modification of the surface active agent-heparin method in which higher quantities of heparin are attached to a plastic surface by using more concentrated solutions of heparin. Likewise, Hu et al., in U.S. Pat. No. 4,865,870, discloses increased heparin attachment by performing the surface active agent heparin complexation at alkaline pH.
Solomon et al., in U.S. Pat. No. 4,713,402, modifies the surface active agent method by exposing the polymeric material to a solution of the surface active agent in a particular chlorofluorocarbon solvent and thereafter exposing the surface to a solution of an antithrombogenic agent, an antibiotic or a mixture thereof
McGary et al. in U.S. Pat. No. 4,678,660 discloses a polyurethane article having coated thereon a layer of polyurethane alloy containing a dispersed complex of a quaternary salt and a carboxy containing antithrombogenic agent or antibiotic. The article is prepared by immersing the substrate in a solvent solution of the complex and the polyurethane alloy.
Plastic tubing rendered antithrombogenic by a phosphonium salt distributed throughout the tubing or coated thereon is disclosed by Gajewski et al. in U.S. Pat. No. 3,759,788.
While the above disclosures have resulted in significant improvements in antithrombogenicity and anti-infectiveness of polymeric surfaces, further improvements are needed. In particular, a method which avoids the use of potentially toxic solvents is needed. It is toward fulfillment of this need that this invention is directed.